Project Summary Natural killer (NK) cells play a well-established role in innate immunity to intracellular pathogens and tumors. However, previous NK cell research has focused on circulating splenic conventional NK (cNK) cells. Our lab recently identified a novel population of tissue-resident NK (trNK) cells in the liver of mice and humans that likely play a previously unrecognized role in human liver immunity and disease. Tissue-resident NK cells have subsequently been shown to reside in a variety of other tissues and to constitute a developmental lineage that is distinct from cNK cells. Tissue-resident NK cells are identified as NK cells that express CD49a and not DX5, which marks cNK cells. Moreover, trNK cells are distinguished from cNK cells based on distinct cytokine production and transcription factor dependencies. The function of trNK cells and the receptors that regulate tissue-residency are both poorly understood. The objective of this research is to identify mechanisms that control the tissue-residency of trNK cells and to investigate the contribution of trNK cells to liver inflammation in mice. Preliminary data shows that LFA-1-deficient mice exhibit a dramatic accumulation of CD49a+ NK cells in the peripheral blood, which suggests that LFA-1 regulates the mobilization of trNK cells. Surprisingly, LFA-1- deficienct mice were also found to harbor increased numbers of splenic and hepatic CD49a+ NK cells. We hypothesize that LFA-1-deficient trNK cells are mobilized from tissues that require LFA-1 for residency and migrate into tissues such as the liver and spleen, which do not require LFA-1 for localization. As a result, we hypothesize that LFA-1 controls the residency of trNK cells in a tissue-specific manner. In order to test this hypothesis, we aim to: 1) identify the origin of mobilized CD49a+ NK cells; 2) identify the function of LFA-1 on trNK cells; 3) determine the role of tissue-resident and mobilized CD49a+ NK cells in a mouse model of immune-mediated hepatitis. The long-term goal of this project is to improve our currently limited understanding of trNK cells in order to potentially provide the foundation for new immunotherapies of human liver disease.